KR100712667B1 - New diaza-bridged heterocycle derivatives and solid-phase preparation method thereof - Google Patents

Abstract

The present invention relates to a novel diaza heterocyclic derivative and a method for preparing a solid phase thereof. Specifically, after reacting various derivatives with amino acids using a bromoacetal resin solid phase as a starting material, Pictet-Spengler (Pictet-) under acidic conditions It is characterized in that the desorption in the solid phase and the target compound are obtained in a one-pot reaction using a Spengler) mechanism.

Description

New diaza-bridged heterocycle derivatives and solid-phase preparation method

The present invention relates to a novel diaza heterocyclic derivative and a method for preparing a solid phase thereof. Specifically, after reacting various derivatives with amino acids using a bromoacetal resin solid phase as a starting material, Pictet-Spengler (Pictet-) under acidic conditions It is characterized in that the desorption in the solid phase and the target compound are obtained in a one-pot reaction using a Spengler) mechanism.

In general, libraries of combinatorial chemistry are simply collections of molecules. These libraries vary not only by chemical species in the library, but also by methods used to generate members of the library or to identify which members interact with the biological target of interest. How to generate and screen libraries in this area is already quite diverse and complex. For example, recent papers on libraries of various combinatorial chemistries include the use of all members of a labeled or unlabeled library (Janda, Proc. Natl. Acad. Sci. USA 91: 10779-10785, 1994). And many techniques (Dolle, J. Com. Chem., 2 (3): 383-433, 2000).

Combination chemistry is possible in both solution and solid phases, but since 1963, Merrifield Resin, a completely new chemical chemistry has been developed that is completely different from the reaction in classical solution phases. It was made the foundation. Since then, many new resins have been made by many researchers, including Wang, and solid-phase chemical reactions have been the source of further development. Of course, early solid phase synthesis was concentrated on peptide and oligonucleotide synthesis, but gradually solid phase synthesis was used as a general and most effective means for generating combinatorial libraries. When the synthesis takes place in the solid phase, it facilitates the simultaneous synthesis of many substances and at the same time can be easily washed off by simply filtering out solvents and excess reagents, making them much easier and faster than reactions in classical solutions. Could be prepared.

On the basis of this historical background, combinatorial chemistry developed rapidly.

The compound library, together with high throughput screening (HTS), is the basis for the rapid discovery of leading substances early in drug development. Therefore, research on the construction of a unique and drug-compound compound library using combinatorial chemical technology, which is a high-efficiency synthesis method, can be said to be a very important basic research field to increase the probability of discovering new drug substances.

In short, combinatorial chemical synthesis is a new field of synthetic technology for the development of new materials and new materials. Whereas conventional classical organic synthesis synthesizes one compound at a time, combinatorial chemical synthesis technology is capable of producing a wider variety of compounds simultaneously. Synthesis or high-efficiency chemical synthesis that can automate multi-step synthesis processes. In addition, the combination chemical synthesis technology has the advantage that the majority of the reaction process is carried out on a solid support, it is possible to automate the continuous multi-step reaction and reaction process, and the separation and purification process of the product is very simple, high efficiency mass assay.

As such, the combination chemical synthesis technology is a new synthesis method that overcomes the inefficiency and inefficiency of the existing synthesis technology, but it cannot be easily applied to the field of organic synthesis. One of the main reasons for this is that chemical reactions on solid supports often cause unwanted side reactions due to the excessive use of most reaction reagents, and due to the limitations of the solvents available depending on the physical properties of the solid support used. The choice of reaction conditions is extremely narrow. Therefore, the synthesis of a compound library using solid phase synthesis is an important requirement for the selection of an appropriate solid phase support and the establishment of appropriate reaction conditions that can minimize chemical reactions and side reactions applicable to the solid phase.

Bromo acetal polystyrene resins, on the other hand, are not commonly used solid supports, but solid phase desorption under acidic conditions, which is a characteristic of solid supports, and active aldehyde groups in the process react with amides and amines to cause intramolecular cyclization reactions. It can act as an important factor. US Molecular Metics Co., Ltd., is a bicyclic peptidomimetic compound library ( J. Med . Chem . 2002 , 45. 7. 1395-1398, PCT WO 01/00210) which is a beta-turn analog using the bromo acetal polystyrene resin Was applied in production to prove its usefulness. In addition, in Korea, the use of bromo acetal polystyrene resin in constructing a peptidomimetic compound library at Sino-Korea Pharmaceutical Co., Ltd. confirmed the advantages of commercial use of bromo acetal polystyrene resin in solid phase synthesis.

As such, despite the important advantages of combinatorial chemistry, the question of how to make a library of compounds is a very important factor from the standpoint of drug development. In addition, the biological activity of the target compound is very important in terms of organic chemical rather than structural and chemical interest, because many of the drugs on the market are derived from natural products can satisfy this need. It is already known that these natural product mimetic compounds can contribute to the development of chemical biology not only for the purpose of drug development but also for basic science (Boldi, AM Curr . Opin . Chem . Biol . 2004 , 8 , 281) . As is well known, the justification of building a compound library is considered sufficient in practical terms.

The compounds shown above show anticancer effects and activity in the nervous system, of which ET-743 is a drug that has been approved on the market as an anticancer agent. Looking at the compounds, it includes a structure commonly found in alkaloids and physiologically active substances commonly found in natural products. Therefore, many researchers have tried to synthesize natural product mimetics having the above physiological activity. However, the method of synthesizing natural product mimics is usually a conventional organic synthetic method, and preparation of derivatives in addition to the target compound has considerable effort and difficulty.

Thus, many peptides have been attempted in the field of synthesis, including peptides, natural products and natural mimetics, and many peptides have been developed since the early 1990s by the Elman group in developing solid phase synthesis of 1,4-benzodiazepines. There has been synthesis of natural and natural mimic libraries, but the scope is quite limited.

Accordingly, the inventors of the present invention, while studying a method capable of efficiently synthesizing a natural product mimetic having a physiologically active, in particular, anti-cancer effect and an active in the nervous system that can treat diseases of the human body, it is common in the natural products Analyze the structures commonly found in alkaloids and physiologically active substances, get clues, establish their core structures, and react amino acids with various derivatives using bromoacetal resin solid phase as a starting material. The library was prepared, and it was confirmed that the synthesis of the leading substance of new drug development can be mass produced more quickly and in various ways, and thus, the present invention was completed.

The present invention seeks to provide novel diaza heterocyclic derivatives.

In addition, the present invention is to provide a method for producing a solid phase of the diaza heterocyclic derivative.

The present invention provides a diaza heterocyclic derivative represented by the following formula (1).

In Chemical Formula 1,

R ₁ is hydrogen;

Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy;

Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₂ -C ₈ alkenyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy; or

Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₂ -C ₈ alkynyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy,

R ₂ is hydrogen or-(X) -R ₃ ,

Where X is NH, NH (CO), CO, (CO) ₂ , SO, SO ₂ or (CH ₂ ) n (n is an integer from 1 to 4),

R ₃ is C ₁ -C ₈ straight or branched alkyl; Alkenyl of C ₂ -C ₈ ; Alkynyl of C ₂ -C ₈ ; C ₃ -C ₈ cycloalkyl; C ₆ -C ₂₀ aryl; A cycloheterocycle of C ₅ to C ₂₀ ; C ₆ -C ₂₀ aryl substituted with halogen; C ₆ ~ C ₂₀ aryl, or halogen substituted C ₆ ~ C of the C ₁ ~ C ₈ substituted with a ₂₀ aryl alkyl; C ₆ ~ C ₂₀ aryl, or halogen substituted C ₆ ~ C ₂₀ aryl group of the C ₂ ~ C ₈ substituted with alkenyl; Alkynyl of C ₆ ~ C ₂₀ aryl, or a C ₂ ~ C ₈ substituted with an aryl of C ₆ ~ C ₂₀ optionally substituted by halogen; Or NA ₁ A ₂ ,

Here, A ₁ or A ₂ are the same as or different from each other independently, and hydrogen; C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with phenyl; Alkenyl of C ₂ -C ₈ ; Or C ₆ -C ₂₀ aryl unsubstituted or substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,

Ar is C ₆ -C ₂₀ aryl unsubstituted or substituted with halogen, hydroxy, amino, C ₃ -C ₈ cycloalkyl or C ₁ -C ₄ alkoxy; or

C ₅ -C ₂₀ cycloheterocycle unsubstituted or substituted with halogen, hydroxy, amino, C ₃ -C ₈ cycloalkyl or C ₁ -C ₄ alkoxy,

Provided that when Ar is phenyl it has one or more substituents.

Preferably, in Formula 1

R ₁ is hydrogen;

C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with one or more groups selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy;

C ₂ -C ₈ alkenyl unsubstituted or substituted with one or more groups selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy; or

C ₂ -C ₈ alkynyl unsubstituted or substituted with at least one group selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy,

X is CO, SO ₂ or CH ₂ ,

R ₃ is C ₁ -C ₈ straight or branched alkyl; A cycloheterocycle of C ₅ to C ₂₀ ; Phenyl substituted with F, Cl or Br; C ₁ -C ₈ straight or branched chain alkyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C ₂ -C ₈ alkenyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C ₂ -C ₈ alkynyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; Or NA ₁ A ₂ ,

Here, A ₁ or A ₂ are the same as or different from each other independently, and hydrogen; C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with phenyl; Alkenyl of C ₂ -C ₈ ; Or phenyl substituted with F, Cl, Br, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,

Ar is indole or dihydroxy phenyl.

The present invention also provides a method for preparing a solid phase of a diaza heterocyclic derivative represented by the formula (1).

Solid phase preparation method of the diaza heterocyclic derivative according to the present invention

1) reacting bromo acetal resin (2) with a primary amine compound to produce a secondary amine compound (3),

2) preparing the compound (4) by condensing the secondary amine compound (3) with an amino acid derivative having a protecting group,

3) reacting compound (4) prepared in step 2) with piperidine to remove the protecting group, reacting with R ₂ compound to prepare compound (5), and

4) reacting the compound (5) with formic acid to intramolecular cyclization, and is represented by the following Scheme 1.

In Scheme 1, R ₁ , R ₂ , and Ar are as defined in Formula 1.

The solid phase preparation method of the diaza heterocyclic derivative according to the present invention will be described in detail step by step.

Bromo acetal resin (2) used as starting material is either commercially available or directly synthesized.

In step 1) , bromo acetal resin is placed in a Robinson 96-well reactor, and 12 kinds of different primary amines are aliquoted at a predetermined position. The reaction mixture was heated and rotated for 12 hours using a rotary oven at a temperature of 60 ° C., and the resin was vacuum dried by washing three times in the order of dimethylformamide (DMF), methanol (MeOH), and dichloromathane (DCM). do. It was confirmed by the chloranyl method that a secondary amine compound was produced.

In step 2) , amino acid with Fmoc (9-fluorenylmethylchloroformate) and HATU (2- (7-Aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ), DIPEA (N, N'-diisopropylethanolamine) is dissolved in DMF, 30 minutes later, aliquoted into a reaction vessel and placed in each 96 wells. After the reaction for 12 hours at room temperature using the rotary oven above, washed three times in the order of DMF, MeOH, DCM and dried in vacuo. HATU is the most effective reagent when considering yield and purity. The completion of the reaction was confirmed by chloranyl method and proceed to the next step.

In step 3) , the compound (4) prepared in step 2) is reacted with piperidine / DMF to remove the protecting group (Fmoc group), and R ₂ compound (carboxylic acid, isocyanate, sulfonimide or aldehyde) ) Condensation reaction. The reaction conditions may vary depending on the type of R ₂ compound.

a) carboxylic acid condensation

Aliquot 25% piperidine / DMF mixed solvent into the reaction vessel, rotate for 1 hour at room temperature to remove Fmoc functional groups, and wash as described above. Eight carboxylic acids were each taken in 3 equivalents to the reaction wells, dissolved in DMF with DIC (diisopropylcarbodiimide, 3 equiv), HOBt (N-hydroxybenzotriazole, 3 equiv) and reacted. Aliquot into 96 well reactor. The reaction is rotated for 12 hours using a rotary oven at room temperature, the resin is washed three times in the order of DMF, MeOH, DCM and dried in vacuo.

b) isocyanate condensation

Prepared in the same manner as in 3a) above except that the isocyanate (3 equivalents) and DIPEA (3 equivalents) are dissolved in a dichloroethane solvent.

c) sulfonamide condensation

Prepared in the same manner as in 3a) except that sulfonamide (3 equivalents) and DIPEA (3 equivalents) are dissolved in a dichloroethane solvent.

d) aldehyde condensation

Aldehyde (3 equivalents) and sodium borohydride (3 equivalents) are dissolved in DMF and added to the resin, followed by rotation reaction at room temperature for 5 hours. The resin is washed three times in the order of DMF, MeOH, DCM and dried in vacuo.

In step 4) , a solid phase desorption reaction and a cyclization reaction are performed in a one-pot reaction using a Pictet-Spengler mechanism under acidic conditions .

The resin is placed in a well-dried reaction vessel, and 100% formic acid is added to each 96 wells, and the reaction is spun at room temperature for 18 hours. After the reaction, the resin is filtered off in a 96 well reaction vessel, and the obtained compound is concentrated on a parallel evaporation device (SpeedVac) and lyophilized to obtain a solid product. Each product is aliquoted and analyzed for purity and product by LC-MS.

In order to explain the Pictet-Spungler mechanism in more detail in the method for producing a diaza heterocyclic derivative of the present invention, the Pictet-Spungler reaction will be described using the case where Ar is indole or dihydroxyphenyl. .

Pictet-spungler type carbon nucleophiles in indole and dihydroxyphenyl can readily attack activated acyllimin intermediates in the presence of acid catalysts.

The Pictet-Spungler mechanism when Ar is indole is shown in Scheme 2, and the Pictet-Sppenger mechanism when Ar is dihydroxyphenyl is shown in Scheme 3.

As shown in Scheme 2, when Ar is an indole, when cyclized by a Pictet-Sppenger reaction with an iminium moiety generated in a daily container from aldehydes and amides protected under acidic conditions, 2 or 3 of indole is cyclized. Two parts of the nucleophilic at the carbon position can attack.

The second carbon position attack can provide the 3,9-diazabicyclo [3.3.1] non-6-en-2-one derivative (1a) as one diastereomer.

The third carbon site attack is believed to produce spiro-5 atom intermediates, cationic migration and hydride elimination. This is because compound (1a) is one regioisomer and diastereomer in this reaction.

The use of pure formic acid allows the formation of the desired backbone in nearly quantitative yield as one diastereomer.

As shown in Scheme 3, when Ar is dihydroxyphenyl, there are two nucleophilic attack moieties (si face and re face) in the daily container with the resulting cyclic imium. The predefined stereochemistry of the alpha-carbon of L-amino acids has a significant effect on the stereochemical results of the diaza heterocycle, since the re face attack is advantageous due to the distance between the nucleophilic carbon and the cyclic imium. Therefore, when Ar is dihydroxyphenyl, it exists only as one diastereomer (1b).

In the solid phase preparation method of the diaza heterocyclic derivatives according to the present invention, a typical compound is shown in Scheme 4 below.

※ Reaction conditions: (i) R ¹ NH ₂ , DMSO, 60 ° C .; (Ii) Fmoc ( N- Boc) TrpOH, HATU, DIPEA, DMF, room temperature); (Iii) Fmoc ( O- DiTBS) DOPA, HATU, DIPEA, DMF, room temperature; (Iii) a) 25% piperidine, room temperature, b) R ³ CO ₂ H, DIC, HOBt, DIPEA, room temperature; (Iii) R ³ NCO, DIPEA, DCE, room temperature; (Iii) neat HCO ₂ H, room temperature; (Iii) neat HCO ₂ H, 60 ° C.

All reactions proceed to a high-efficiency synthesizer of 96 units, producing 96 compounds per series.

The diaza heterocyclic derivatives according to the present invention include structures commonly found in alkaloids and physiologically active substances commonly found in natural products, and thus have anti-cancer effects, antiviral, anti-inflammatory, cardiovascular diseases, and immune diseases. It is expected to have pharmacological activity in diseases of the central nervous system and the like.

In addition, the method for producing a solid phase of a diaza heterocyclic derivative according to the present invention using a Pictet-Spengler mechanism under acidic conditions after reacting amino acids and various derivatives using a bromoacetal resin solid phase as a starting material. In the one-pot reaction, the target compound can be obtained through desorption in the solid phase and intramolecular cyclization. Therefore, several kinds of compound libraries can be prepared at the same time, and the production method can lead to faster and more diverse mass production of leading substances in drug development.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited thereto.

Starting materials, reactants and solvents are described in Aldrich Chemical Co. (Milwaukee, WI) and used without further purification. Bromoacetal solid phase supports were purchased from Advanced ChemTech. ¹ H NMR spectra were recorded at Bruker Avance 300 MHz and Varian 500 MHz, and chemical shifts (δ) were recorded in ppm relative to TMS as an internal standard. All samples were dissolved in DMSO and CDCl ₃ unless otherwise specified. LC-MS data was recorded on the Micromass platform. Parallel solid phase synthesis was used to purchase a FlexChem ^® Synthesis System from captured (Sunnyvale, CA) SciGene.

Example  One  : According to the present invention Diaza  Of heterocyclic derivatives Solid phase  Manufacturing method

1. Amine Substitution

Bromo acetal resin (40 mg, 1.6 mmol / g, 0.064 mmol) was placed in a Robinson 96-well reactor, and 12 different primary amines (20 equiv. In DMSO 1.2 mL) were aliquoted at predetermined locations. . The reaction mixture was heated and rotated for 12 hours using a rotary oven at 60 ℃. The resin was washed three times in the order of DMF, MeOH, DCM and vacuum dried.

2. Amino Acids Condensation

Fmoc-Trp (Boc) -OH or Fmoc-L-DOPA (DiTBS) -OH (3 equiv), HATU (3 equiv) and DIPEA (6 equiv) dissolved in DMF (1.2 mL per well) after 30 min Were aliquoted and placed in each 96 wells. The reaction mixture was reacted for 12 hours at room temperature using the rotary oven above. The resin was washed three times in the order of DMF, MeOH, DCM and dried in vacuo.

3. Carboxylic acid , Isocyanate, Sulfonamide  Or aldehyde Condensation

a) carboxylic acid condensation

A 25% piperidine / DMF mixed solvent was aliquoted into the reaction vessel and rotated at room temperature for 1 hour. The resin was washed three times in the order of DMF, MeOH, DCM and then again with DMF. Eight carboxylic acids were each taken in three equivalents to the reaction wells, dissolved in DMF together with DIC (3 equivalents) and HOBt (3 equivalents) and allowed to react for 30 minutes. The reaction mixture was aliquoted into a 96 well reactor and spun for 12 hours using a rotary oven at room temperature. The resin was washed three times in the order of DMF, MeOH, DCM and dried in vacuo.

b) isocyanate condensation

Prepared in the same manner as in 3a) except that isocyanate (3 equivalents) and DIPEA (3 equivalents) were dissolved in a dichloroethane solvent instead of the carboxylic acid in a).

c) sulfonamide condensation

Prepared in the same manner as in 3a), except dissolving sulfonamide (3 equivalents) and DIPEA (3 equivalents) in a dichloroethane solvent instead of carboxylic acid in a).

d) aldehyde condensation

The same as in 3a) except that aldehyde (3 equivalents) and sodium borohydride (3 equivalents) instead of carboxylic acid in a) are dissolved in DMF and added to the resin, followed by rotation reaction at room temperature for 5 hours. To make.

4. Solid phase Desorption reaction  And cyclization reactions

The resin was placed in a well-dried reaction vessel, and 100% formic acid (1.2 mL) was added to each 96 wells, followed by rotation reaction at room temperature for 18 hours. After the reaction, the resin was filtered off in a 96-well reaction vessel, and the obtained compound was concentrated on a parallel evaporation device (SpeedVac) and freeze-dried to obtain a solid product. The resulting product was diluted with 50% water / acetonitrile and lyophilized to give an off-white powder. Each product was aliquoted and analyzed for purity and product by LC-MS.

Hereinafter, the structure and analytical data of the diaza heterocyclic derivatives prepared by the preparation method of Example 1 are shown in Table 1 below.

The purity and molecular weight of the representative compounds of the compounds shown in Table 1 are shown in Table 2.

Compound number water(%) Theoretical molecular weight Actual molecular weight 26 96.7 503.18 504.03 40 97.4 466.19 466.77 232 86.3 458.48 459.87 94 95.6 411.16 412.06 235 99.2 484.54 485.93 105 93.7 481.22 481.09 295 91.4 487.55 488.85 118 95.1 401.19 401.11 307 96.7 437.49 438.88 144 94.6 535.30 535.19 336 88.1 527.65 528.95 361 90.26 429.90 430.82

Example  2  : 4,5-dihydroxy-11,13-diaza-tricyclo [7.3.1.0 ^2.7 ] Preparation of Trideca-2 (7), 3,5-trien-10-one: Manufactured by General Organic Synthesis Method

Dissolve Boc- L- DOPA-OH (3.5 g, 11.78 mmol) in dichloromethane (250 mL), diisopropylcarbodiimide (1.9 mL, 11.78 mmol), hydroxybenzotriazole (1.8 g, 11.78) , Diisopropylethylamine (4 mL, 23.56 mmol) was added and stirred at room temperature for 30 minutes. Aminoacetaldehyde (1.71 mL, 11.78 mmol) was added to this reaction mixture and stirred at rt for 3 h. After completion of the reaction, the organic layer was washed with 10% citric acid aqueous solution, and then the organic layer was removed with sodium sulfate. After concentrating the mixed solvent, the compound was added to pure formic acid and stirred for 15 hours to complete the reaction and then concentrated formic acid. The resulting compound was purified using silica gel to obtain 1.1 g of the target compound solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.35 (d, J = 3.5, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 5.35 (s, 1H), 5.34 (s, 1H) , 4.00 (d, J = 3.4, 1H), 3.6 (m, 3H), 3.05 (dd, J = 11.8, 3.8, 1H), 2.95 (dd, J = 16.0, 6.1,1H) 2.62 (d, J = 17.4, 1 H);

MS (ESI ⁺ ) m / z 220.90 [M + H] ⁺ .

Diaza heterocyclic derivatives according to the present invention is a bromoacetal resin solid phase as a starting material and the amino acid and various derivatives after the reaction using a Pictet-Spengler mechanism under acidic conditions (one- In the pot reaction, the target compound can be obtained through desorption in the solid phase and intramolecular cyclization. Therefore, several kinds of compound libraries can be prepared at the same time, and by this preparation method, there is an effect that it is possible to produce mass-produced leading substances in new drug development more quickly and variously.

Claims (3)

Diaza heterocyclic derivative represented by the following formula (1). <Formula 1>

In Chemical Formula 1, R ₁ is hydrogen; Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy; Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₂ -C ₈ alkenyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy; or Halogen, hydroxy, mercapto, amino, C ₁ to C ₄ alkylamino, C ₁ to C ₄ dialkylamino, C ₁ to C ₄ alkylthio, C ₁ to C ₄ alkylsulfinyl, C ₁ Alkylsulfonyl of ˜C ₄ , C ₁ ˜C ₄ alkoxy, cycloalkyl of C ₃ ˜C ₈ , aryl of C ₆ ˜C ₂₀ , cycloheterocycle of C ₅ ˜C ₂₀ , and halogen, CF ₃ or C C ₂ -C ₈ alkynyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₆ -C ₂₀ aryl substituted with ₁ -C ₄ alkoxy, R ₂ is hydrogen or-(X) -R ₃ , Where X is NH, NH (CO), CO, (CO) ₂ , SO, SO ₂ or (CH ₂ ) n (n is an integer from 1 to 4), R ₃ is C ₁ -C ₈ straight or branched alkyl; Alkenyl of C ₂ -C ₈ ; Alkynyl of C ₂ -C ₈ ; C ₃ -C ₈ cycloalkyl; C ₆ -C ₂₀ aryl; A cycloheterocycle of C ₅ to C ₂₀ ; C ₆ -C ₂₀ aryl substituted with halogen; C ₆ ~ C ₂₀ aryl, or halogen substituted C ₆ ~ C of the C ₁ ~ C ₈ substituted with a ₂₀ aryl alkyl; C ₆ ~ C ₂₀ aryl, or halogen substituted C ₆ ~ C ₂₀ aryl group of the C ₂ ~ C ₈ substituted with alkenyl; Alkynyl of C ₆ ~ C ₂₀ aryl, or a C ₂ ~ C ₈ substituted with an aryl of C ₆ ~ C ₂₀ optionally substituted by halogen; Or NA ₁ A ₂ , Here, A ₁ or A ₂ are the same as or different from each other independently, and hydrogen; C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with phenyl; Alkenyl of C ₂ -C ₈ ; Or C ₆ -C ₂₀ aryl unsubstituted or substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, Ar is C ₆ -C ₂₀ aryl unsubstituted or substituted with halogen, hydroxy, amino, C ₃ -C ₈ cycloalkyl or C ₁ -C ₄ alkoxy; or C ₅ -C ₂₀ cycloheterocycle unsubstituted or substituted with halogen, hydroxy, amino, C ₃ -C ₈ cycloalkyl or C ₁ -C ₄ alkoxy, Provided that when Ar is phenyl it has one or more substituents. According to claim 1, in the formula 1 R ₁ is hydrogen; C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with one or more groups selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy; C ₂ -C ₈ alkenyl unsubstituted or substituted with one or more groups selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy; or C ₂ -C ₈ alkynyl unsubstituted or substituted with at least one group selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF ₃ or methoxy, X is CO, SO ₂ or CH ₂ , R ₃ is C ₁ -C ₈ straight or branched alkyl; A cycloheterocycle of C ₅ to C ₂₀ ; Phenyl substituted with F, Cl or Br; C ₁ -C ₈ straight or branched chain alkyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C ₂ -C ₈ alkenyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C ₂ -C ₈ alkynyl substituted with a group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; Or NA ₁ A ₂ , Here, A ₁ or A ₂ are the same as or different from each other independently, and hydrogen; C ₁ -C ₈ straight or branched chain alkyl unsubstituted or substituted with phenyl; Alkenyl of C ₂ -C ₈ ; Or phenyl substituted with F, Cl, Br, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, Ar is a diaza heterocyclic derivative wherein indole or dihydroxy phenyl. 1) reacting bromo acetal resin (2) with a primary amine compound to produce a secondary amine compound (3), 2) preparing the compound (4) by condensing the secondary amine compound (3) with an amino acid derivative having a protecting group, 3) reacting compound (4) prepared in step 2) with piperidine to remove the protecting group, reacting with R ₂ compound to prepare compound (5), and 4) A method for producing a solid phase of a diaza heterocyclic derivative represented by the following Scheme 1, characterized by the step of reacting the compound (5) with formic acid in the molecule. <Scheme 1>

In Scheme 1, R ₁ , R ₂ , and Ar are as defined in Formula 1.